Angiogenesis and fibrosis are key components in development, growth, wound healing, and regeneration (Klagsbrun & D'Amore, (1991) Annu. Rev. Physiol. 53, 217–239). In addition, these processes commonly occur together in many disease states where neovascularization is believed to initiate the pathological cascade, including proliferative diabetic retinopathy (Aiello et al. (1998) Diabetes Care 21, 143–156), rheumatoid arthritis (Firestein (1999) J. Clin. Invest. 103, 3–4), and age-related macular degeneration (Lopez et al. (1996) Invest. Ophthalmol. & Visual Sci. 37, 855–868).
Vascular endothelial growth factor (VEGF) is expressed as a family of peptides of 121, 145, 165, 189, and 206 amino acid residues. Its expression is induced by hypoxia and is essential in the vasculogenesis process during development. Several receptors have been shown to mediate the action of VEGF, and most of them belong to the tyrosine kinase receptor family (Petrova et al. (1999) Exp. Cell Res. 253, 117–130). Upon the binding of VEGF to its receptors, multiple signaling cascades are activated, including the tyrosine phosphorylation of phospholipase Cγ, elevation of intracellular calcium and diacylglycerol, activation of protein kinase C (PKC), and extracellular signal-regulated kinase (MAPK/ERK) for endothelial cell proliferation. In addition, VEGF also stimulates activation of phosphatidylinositol (PI) 3-kinase leading to Akt/PKB activation and possibly enhancing endothelial cell survival.
Connective tissue growth factor (CTGF) is a potent and ubiquitously expressed growth factor that has been shown to play a unique role in fibroblast proliferation, cell adhesion, and the stimulation of extracellular matrix production (Frazier et al. (1996) J. Invest. Dermatol. 107, 404–411; Kireeva et al. (1997) Exp. Cell Res. 233, 63–77). The 38-kDa protein was originally identified in conditioned medium from human umbilical vein endothelial cells, and the expression was shown to be selectively stimulated by transforming growth factor-β (TGF-β) in cultured fibroblasts. Due to its mitogenic action on fibroblasts and its ability to induce the expression of the extracellular matrix molecules, collagen type I, fibronectin, and integrin α5, CTGF is supposed to play an important role in connective tissue cell proliferation and extracellular matrix deposition as one of the mediators of TGF-β. CTGF also seems to be an important player in the pathogenesis of various fibrotic disorders, since it was shown to be overexpressed in scleroderma, keloids, and other fibrotic skin disorders (Igarashi et al. (1996) J. Invest. Dermatol. 106, 729–733), as well as in stromal rich mammary tumors, and in advanced atherosclerotic lesions. Recently, the integrin α5β3 has been reported to serve as a receptor on endothelial cells for CTGF-mediated endothelial cell adhesion, migration, and angiogenesis (Babic et al. (1999) Mol. Cell. Biol. 19, 2958–2966).
Besides TGF-β, the expression of CTGF is reported to be regulated by dexamethasone in BALB/c 3T3 cells, high glucose in human mesangial cells, kinin in human embryonic fibroblasts, factor VIIa, and thrombin in WI-38 fibroblasts, tumor necrosis factor α in human skin fibroblast, and cAMP in bovine endothelial cells (Dammeier et al. (1998) J. Biol. Chem. 273, 18185–18190; Murphy et al. (1999) J. Biol. Chem. 274, 5830–5834; Ricupero et al. (2000) J. Biol. Chem. 275, 12475–12480; Pendurthi et al. (2000) J. Biol. Chem. 275, 14632–14641; Abraham et al. (2000) J. Biol. Chem. 275, 15220–15225; Boes et al. (1999) Endocrinology 140, 1575–1580).